Spinal bulbar muscular atrophy (SBMA), also known as Kennedy's disease, Kennedy's syndrome, bulbospinal muscular atrophy, and X-linked recessive spinal bulbar muscular atrophy, is a slowly progressive neuromuscular disorder that strikes people, primarily men, in late adulthood. It is characterized by progressive muscle weakness including bulbar signs, facial fasciculations, dysphagia, numbness, reduced reflexes, tremor, reduced androgen sensitivity, severe cramps, hypothalamic defect, problems with speech and swallowing, as well as lower motor and primary sensory neuropathy. With this disease, muscle weakness and wasting is generally noted in the lower body and eventually spreads to the upper extremities over time.
SBMA is known to be caused by a genetic mutation in the androgen receptor gene on the X chromosome in humans. SBMA is recessive in nature, in that only males tend to develop SBMA, and not females. Females have two X chromosomes whereas males have only a single X chromosome. Thus, female carriers of SBMA have two copies of the androgen receptor gene—one mutated copy and one good copy. The presence of a normal androgen receptor gene on one X chromosome in female carriers may protect such females from developing full blown symptoms of the disease. Alternatively, females also have a much lower level of androgens than males and this low level of androgens is likely to be a critical factor for why females tend to not show SBMA, given that even females with two bad copies of the androgen receptor gene also show little or no symptoms of SBMA. On other hand, each male born from a carrier female (one good copy and one bad copy of the androgen receptor gene) has a fifty percent chance of inheriting the gene and developing the disease. This high percentage is based on the fact that males receive their only X chromosome from their mother and if this X chromosome has the mutated gene, they will one day develop the symptoms of SBMA.
The X-linked genetic mutation is an expansion of a CAG trinucleotide repeat in the coding region of the androgen receptor (AR) gene. The CAG trinucleotide is repeated up to 34 times in a normal AR gene. Any amount greater than 35 CAGs constitutes an expansion of the trinucleotide repeat. The abnormally expanded CAG trinucleotide repeat changes the structure of the AR protein produced by the AR gene. The resulting AR protein has a longer string of glutamines (polyglutamine repeats), which if substantial enough, can lead to SBMA in adulthood. Recent evidence based on animal studies suggests that androgens such as testosterone, dehydroepiandrosterone, androstenedione, androstanediol, androsterone, dihydrotestosterone and other steroid hormones can trigger the symptoms of SBMA when they interact with androgen receptors. How polyglutamine tract expansion leads to neurodegeneration in SBMA and other polyglutamine tract diseases is still unknown.
SBMA is widely presumed to be caused by the death of motoneurons, eventually leading to the atrophy of muscles. It is currently believed that the abnormally expanded CAG trinucleotide repeats, and the resulting changes in the structure of the AR protein, disrupt the normal function of motoneurons in the brain and spinal cord leading to SBMA. It is currently held that as these motoneurons gradually die, weakness, wasting and general deterioration of muscles develop as secondary consequences of the motoneuron degradation.
Although SBMA has a known genetic cause, there is currently no cure for SBMA sufferers. Patients afflicted by this disease must resort to physical therapy and speech/swallowing therapy to help control symptoms. Several efforts to compensate for loss of normal androgen receptor function through androgen replacement therapy have failed. Current research focuses on unraveling the mutant receptor's toxic gain of function (when a protein becomes toxic because of a gene flaw) and designing treatments to inhibit that function. Currently, all administered treatments are designed to mitigate the effects of failing muscles and curb the discomfort of patients through pain management.
At the present time, there are no known spontaneous animal mutations with sufficient similarities to SBMA to be useful as experimental models. In order to yield useful information on etiology or treatment of SBMA, appropriate animal models must be developed. With appropriate animal models, researchers can develop methods of treatment that effectively combat the symptoms of SBMA. SBMA animal models also will allow researchers to develop treatments that terminate the progression of the disease and possibly reverse symptoms.